It is the principle purpose of the immune system to protect the host from infectious pathogenic microorganisms. With that purpose in mind, lymphocytes have been programmed to differentiate self tissue antigens from foreign antigen. However, the appearance of autoimmune diseases and the presence of autoreactive lymphocytes in the normal population illustrates that the regulation of immunity is far from perfect. Systemic autoimmune diseases are the product of a complex interaction of lymphocytes, soluble macromolecules, and self tissues leading to the pathology of disease. Autoimmune responses often target multiple determinants within an autoantigen. For example, in systemic lupus erythematosus (SLE), autoantibodies are directed at a number of determinants on small nuclear ribonucleoproteins (snRNPs) and on nucleosomes. The self or foreign proteins involved in the spontaneous initiation of these autoimmune responses is not known. We have recently identified the ability of a novel post- translational protein modification, termed isoaspartyl, to confer autoimmunity to otherwise immunologically inert self peptides. For example, the immunization with isoaspartyl forms of snRNPs can provoke autoantibody responses typical of human SLE. Isoaspartyl peptide modifications arise frequently in aged and stressed cells. This proposal will examine the presence of isoaspartyl forms of lupus autoantigens in resting, aged, and activated lymphocyte populations and determine their ability to circumvent immune tolerance. Second, we will examine the immunologic abnormalities, lymphokine responses and intracellular signalling, in murine models unable to repair isoaspartyl modifications (PIMT knockout mice). Finally, we will study the progression of spontaneous lupus autoimmunity and pathology in MRL lpr/lpr-PIMT-/- mice, a murine model of human SLE. This proposal will define the biological and immunological implications of post-translational protein modifications. Overall, our studies will address mechanisms important in the induction and perpetuation of autoimmune disease. A more thorough understanding of the earliest events in the genesis of autoimmunity may help identify important elements to exploit for the immunologic intervention of these diseases.